{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:37:48Z","timestamp":1792460268775,"version":"4.5.0"},"reference-count":46,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017389","name":"VCRC","doi-asserted-by":"crossref","award":["http:\/\/www.vasculitisfoundation.org\/research\/research-program\/"],"award-info":[{"award-number":["http:\/\/www.vasculitisfoundation.org\/research\/research-program\/"]}],"id":[{"id":"10.13039\/100017389","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody\u2013associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3\u2013reactive (PR3\n                      <jats:sup>+<\/jats:sup>\n                      ) B cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3\n                      <jats:sup>+<\/jats:sup>\n                      B cells (total and subsets).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      The frequency of PR3\n                      <jats:sup>+<\/jats:sup>\n                      B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%\u20136.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%\u20135.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%\u20132.16%],\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3\n                      <jats:sup>+<\/jats:sup>\n                      B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3\n                      <jats:sup>+<\/jats:sup>\n                      memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3\n                      <jats:sup>+<\/jats:sup>\n                      B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3\n                      <jats:sup>+<\/jats:sup>\n                      B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate,\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05) and complete remission (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT00104299.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.150999","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T12:12:16Z","timestamp":1633608736000},"source":"Crossref","is-referenced-by-count":22,"title":["Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-921X","authenticated-orcid":true,"given":"Alvise","family":"Berti","sequence":"first","affiliation":[{"name":"Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA."},{"name":"Rheumatology Unit, S. 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